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J. Biol. Chem., Vol. 277, Issue 47, 45249-45258, November 22, 2002
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From the The polypeptide hormone stanniocalcin (STC) is
widely expressed in mammalian tissues. STC acts locally in kidney and
gut to modulate calcium and phosphate excretion, and its overexpression in mice results in high serum phosphate, dwarfism, and increased metabolic rate. STC has also been linked to cancer, pregnancy, lactation, angiogenesis, organogenesis, cerebral ischemia, and hypertonic stress. In this report we have characterized the STC receptor and the functional targeting of ligand and receptor to mitochondria. For receptor binding analysis, a stanniocalcin-alkaline phosphatase fusion protein was engineered. Subsequent binding assays
using the fusion protein indicated that kidney and liver contained the
highest number of binding sites with affinities of 0.8 and 0.25 nM, respectively. Intriguingly, purified mitochondria from both tissues yielded similar high affinity binding sites. Fractionation analysis revealed that the majority of binding sites were
localized to the inner mitochondrial membrane. In further studies, we
characterized the time course of STC-alkaline phosphatase fusion
protein sequestration by intact mitochondria. In situ
ligand binding also revealed discrete, displaceable binding to plasma membranes and mitochondria of nephron cells and liver hepatocytes. The
existence of mitochondrial receptors prompted a similar search for the
ligand. Immunogold electron microscopy revealed that STC was
preferentially concentrated in the mitochondria of all nephron segments
targeted by STC. Subcellular fractionation revealed that >90% of
cellular STC immunoreactivity was mitochondrial, confined to the inner
matrix, and similar in size to recombinant STC (50 kDa). In functional
studies, recombinant STC had concentration-dependent stimulatory effects on electron transfer by sub-mitochondrial particles. Collectively the evidence implies a role for STC in cell metabolism.
Characterization of Mammalian Stanniocalcin Receptors
MITOCHONDRIAL TARGETING OF LIGAND AND RECEPTOR FOR REGULATION
OF CELLULAR METABOLISM*
,, and Department of Biology, Faculty of Science,
and the § Department of Physiology, Faculty of Medicine
and Dentistry, The University of Western Ontario,
London, Ontario N6A 5C1, Canada
*
The work was supported by the Kidney Foundation of Canada
and The Canadian Institutes of Health Research.The costs of publication of this
article were defrayed in part by the
payment of page charges. The article
must therefore be hereby marked
"advertisement" in accordance with 18 U.S.C. Section
1734 solely to indicate this fact.
Copyright © 2002 by The American Society for Biochemistry and Molecular Biology, Inc.
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